The sudden infant death syndrome (SEDS) is the leading cause of postneonatal infant mortality, with an overall incidence of 0.8/1000 live births. Its cause(s) is unknown. Based upon our brainstem studies in SIDS victims during the last grant cycle, we propose an expanded hypothesis concerning the role of the ventral medulla, a region related to chemoreception, autonomic responses, respiratory drive, and thermoregulation, and the neurotransmitter, serotonin (5- HT) in the pathogenesis of SIDS: SIDS, or a subset of SIDS, is due to a developmental abnormality in a ventral medullary network composed of rhombic lip-derived, serotonergic neurons, and this abnormality results in a failure of protective responses to life-threatening challenges (e.g., asphyxia, hypoxia, hypercapnia) during sleep, hi Specific Aims 1-3, we will characterize the normal development of the 5-HT ventral medullary network in brain tissues across early life, the time-period of the pathogenesis of SIDS. We will utilize selected markers to 5-HT cells, terminals, receptor subtypes, and the synthetic enzyme, tryptophan hydroxylase, using tissue autoradiography, immunocytochemistry, and in situ hybridization in brain tissues from human embryos, fetuses, and infants. We will then determine how 5-HT development is abnormal in SIDS victims compared to age-matched controls with the same. 5-HT markers. In Specific Aim 4, we will establish which cell populations derive from the human rhombic lip using cellular and molecular markers to transcription factors implicated in rhombic lip-derivation in animal studies, and we will determine if the affected nuclei in the ventral medullary network in SIDS victims derive from this same embryonic anlage. We will determine if there is an abnormal number of neurons and reactive astrocytes (gliosis) in selected rhombic lip-derived nuclei in SIDS victims. We predict that we will not find gliosis (scarring) in these nuclei, suggesting a developmental, rather than degenerative, defect. Theproposed studies should: substantiate a 5-HT defect in the ventral medulla of SIDS victims; provide insight into the normal development and the molecular and chemical anatomy of the human 5-HT ventral medullary network; and suggest clues about abnormal function in SIDS victims for testing in animal models, and for devising specific preventive strategies and diagnostic tests in human infants.